When a major structural malformation is found, such as an atrioventricular canal defect or a double‐bubble suggestive of duodenal atresia, the risk of trisomy 21 in that pregnancy is increased by approximately 20–30‐fold. For many patients, such an increase in their background risk for aneuploidy will be sufficiently high to justify genetic amniocentesis.
Sonographic detection of minor features of aneuploidy
Second‐trimester sonography can also detect a range of minor features or “markers” suggestive of aneuploidy. These are not structural abnormalities of the fetus per se but are associated with an increased probability that the fetus is aneuploid. These minor markers are typically much more common than structural abnormalities and likelihood ratios based on the presence or absence of these markers have been used to adjust each patient’s risk of having a fetus with trisomy 21. However, with improvements in aneuploidy screening, including serum and combined methods as well as cfDNA screening, these minor findings add little to the detection of chromosomal abnormalities. Rather, when screening results indicate a low risk of aneuploidy, these markers are most commonly normal variants. The one possible exception is a thickened nuchal fold, which is uncommon in euploid fetuses and therefore has a low false‐positive rate and relatively high specificity for Down syndrome. In cases in which multiple markers are seen, the risk of aneuploidy is higher and genetic counseling may be indicated. Table 5.2 also summarizes the minor sonographic markers that, when visualized, may increase the probability of an aneuploid fetus.
Second‐trimester AFP, hCG, uE3, and inhibin‐A
Maternal serum levels of AFP (MSAFP) and unconjugated estriol (uE3) are both approximately 25% lower, and levels of hCG and inhibin‐A approximately twice as high in pregnancies complicated by trisomy 21. MSAFP, uE3, and hCG all tend to be decreased in pregnancies complicated by trisomy 18. The combination of AFP, uE3, hCG and inhibin‐A, commonly known as the quad screen, can detect about 80% of cases of trisomy 21, at a 5% false‐positive rate. Quad marker screening has the additional advantage of also screening for neural tube defects given the inclusion of MSAFP. Performance of serum screening tests is optimized by accurate ascertainment of gestational age, and, wherever possible, sonographic dating should be used instead of menstrual dating.
Combined first‐ and second‐trimester screening
In some programs, multiple markers in both the first and second trimesters are combined to optimize screening performance. The most common approaches include sequential screening, in which first‐trimester combined (serum and NT measurement) screening is performed and results provided. High‐risk patients are offered follow‐up with either cfDNA or diagnostic testing; patients at any risk level can also go on to have quad screening and be provided a final result including all serum analytes as well as the NT. This approach is associated with a 90–95% detection rate for trisomy 21 at a 5% false‐positive rate. It has the advantage of a high detection rate, the provision of a first‐trimester result, and the ability to screen for neural tube defects.
Integrated screening involves the same two‐step screening protocol, but results are not released until all screening steps are completed. This results in a lower false‐positive rate but has the disadvantage of later provision of results. A serum integrated screening approach, including first and second trimester serum analytes, can also be used in patients who do not have access to NT measurement. Again, this has the advantage of a relatively high detection rate but provides a later result.
Conclusion
A wide range of screening tests for fetal aneuploidy, in particular trisomy 21, is now available in both the first and second trimesters. Cell‐free DNA‐based tests are more targeted and precise for the common aneuploidies, so are more appropriate for women at high risk for aneuploidy. Serum‐based tests have higher false‐positive rates but can detect risk for a broader array of abnormalities and therefore have some advantages for women at low risk for aneuploidy. No one approach is best, but concurrent use of serum and cfDNA screening can lead to confusion among patients and providers and should be avoided. All pregnant patients should be provided with pretest counseling to select the most appropriate screening or diagnostic test for their particular circumstances. Rapid developments in the field mean that test options and guidelines are constantly evolving.
Suggested reading
1 American College of Obstetricians and Gynecologists. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. Obstet Gynecol 2012; 120:1532–34.
2 American College of Obstetricians and Gynecologists. Practice Bulletin No. 162. Prenatal diagnostic testing for genetic disorders. Obstet Gynecol 2016; 127:e108–22.
3 Bianchi DW, Crombleholme TM, d’Alton ME, Malone FD. Fetology: Diagnosis and Management of the Fetal Patient, 2nd edn. New York: McGraw Hill, 2010.
4 Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell‐free DNA in maternal blood in screening for aneuploidies: updated meta‐analysis. Ultrasound Obstet Gynecol 2017; 50(3):302–14.
5 Kaimal AJ, Norton ME, Kuppermann M. Prenatal testing in the genomic age: clinical outcomes, quality of life, and costs. Obstet Gynecol 2015; 126(4):737–46.
6 Malone FD, Canick JA, Ball RH, et al. A comparison of first trimester screening, second trimester screening, and the combination of both for evaluation of risk for Down syndrome. N Engl J Med 2005; 353:2001–11.
7 Norton ME, Jacobsson B, Swamy GK, et al. Cell‐free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015; 372(17):1589–97.
8 Nyberg DA, Souter VL. Chromosomal abnormalities. In: Nyberg DA, McGahan JP, Pretorius DH, Pilu G (eds) Diagnostic Imaging of Fetal Anomalies. Philadelphia: Lippincott Williams & Wilkins, 2003; pp. 861–906.
9 Palomaki GE, Kloza EM, Lambert‐Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.
